Associate Professor, M.D, D.T.M, A.F.I.M Consultant Internist Gastroenterologist College of Medicine...

DR. MOHAMED ISMAIL YASAWY

Associate Professor, M.D, D.T.M, A.F.I.M

Consultant Internist GastroenterologistCollege of Medicine

Dammam University Hospital, Al-Khobar

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Views

Crohn’s Disease Activity Index (C.D.A.I) is the most commonly used clinical assessment criteria

Harvey Bradshaw scoring system is more easily applicable than C.D.A.I

For well control C.D long term steroid therapy is the usual requirement

5ASA is essential for maintaining remission in C.D

Antibiotics i.e. Metronidazole and Cipro are essential in the treatment of C.D

Immunosuppressive e.g. Azothioprin are relatively effective for both induction of remission and maintaining the remission in C.D

ATNF (Biological agent) are used mainly as a curative treatment

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CROHN’S DISEASE

What is Crohn’s Disease?

A serious Gastrointestinal chronic G.I Problem with

Exacerbation & Remission associated with life

threatening complications.

Crohn’s disease encompasses a spectrum of clinical and pathological patterns manifested by focal, asymmetric, transmural, and, occasionally, granulomatous inflammation affecting the gastrointestinal tract with the potential for systemic and extraintestinal complications.Data on file, Centocor.

Hanauer S et al. Am J Gastroenterol. 2001; 96: 635-643.

Large Intestine (Colon)

StomachSmall Intestine

Esophagus

Rectum

CROHN’S DISEASEWhat is Crohn’s Disease?

The incidence is evenly divided between UC & CD.

Approximately 10 to 20 %of pts will present with initial diagnosis of indeterminate colitis because a primary diagnosis is not possible.

CROHN’S DISEASE

Introduction

IBD

UC CD

Susceptibility Genes Environmental Factors

Environmental factors Environmental factors

Disease Specificity Genes

Genes DeterminingPhenotype

CROHN’S DISEASE

IBD – Aetiologic Concepts

In 1932, Crohn Ginzberg and Oppenheimer described this disease and noted it’s localization to segment of the ileum. It was later noted that Crohn’s Disease may involve any part of the (G.I) tract.

Crohn’s Disease is an idiopathic, chronic, transmural inflammatory process. It can affect any part of the gastrointestinal (G.I) tract from the mouth to the Anus.

CROHN’S DISEASEIntroduction

The condition is believed to be the result of an imbalance between pro-inflammatory and anti-inflammatory medias. Most C.D cases involves the small bowel particularly the terminal ileum.

CROHN’S DISEASE

Introduction

The exact cause of C.D remains unknown. Current theories implicate the role of genetic, microbial, immunological, environmental, dietary, vascular and even psychosocial factors as a causative agent. It has been suggested that, patients have an inherited susceptibility for an aberrant immunologic response to one or more of these provoking factors.

CROHN’S DISEASE

IBD - Aetiologic Concepts

IBD: PATHOGENESIS

Infection

Diet

Smoking

NSAIDs

Genetic susceptibility

Immune dysregulation

Environmental trigger

TH 1

TH 2

IBD

Chromosome 16 (IBD1)

Chromosome 12 (IBD2)

Chromosome 6 (IBD3-HLA)

Chromosome 14

NOD2

Ahmad et al, Aliment Pharmacol Ther 2001; Hugot et al, Science 2001

CROHN’S DISEASE

Incidence 5-15 / 100 000 population1

Prevalence 9 – 199 / 100 000 population1

1 Marshall JK and Hilsden RJ. Chapter 2. In: Satsangi J, Sutherland LR, eds. Inflammatory Bowel Diseases. 1st ed. Churchill Livingstone, Elsevier; 2003. p.18 2 Economou M and Pappas G. Inflammatory Bowel Diseases. 2008; 14: 709-720.

Global map of CD2

Annual incidence:- red >7/105

- orange 4-7/105

- green1-4/105

- blue <1/105

- white: absence of data

CROHN’S DISEASE

Crohn’s Disease - Presentation

Inflammatory• Pain, tenderness, diarrhea, RLQ mass

Obstruction• Cramps, distension, vomiting,

obstruction

Fistulizing• Enterocoutaneous, enteroenteric,

rectovaginal, enterovesical, etc.

CROHN’S DISEASE

Diarrhea Abdominal pain and tenderness Weight loss Fever Fatigue Rectal bleeding Nausea Anorexia

Knutson D et al. Am Fam Physicians. 2003; 68: 707-718.

CROHN’S DISEASE

Common Symptoms Of Crohn’s Disease

It is not IBS

Arthritis Axial – Ankylosing

Spondylitis Peripheral

Skin Erythema

nodosum Pyoderma

gangrenosum Eyes

Anterior uveitis Episcleritis/Iritis

Liver PSC Autoimmune

hepatitis

CROHN’S DISEASEExtra G.I Manifestaions

Uncommon <1% of IBD pts

Sterile ulcerating skin lesions

Overhung violaceous borders

Exhibits pathergy May be independent of

IBD May be difficult to treat

Characteristic skin rash - raised nodules on shins

Septal panniculitis in subcutis May occur in up to 10% of

patients, depending on study population

CD>>UC F>>M (5:1) Often occurs with relapse of

IBD

? More common in colonic disease

Associated with other EIMs

Arthritis, uveitis

Sweet’s Syndrome

Acute red eye associated with relapse of IBD

Usually iritis or anterior uveitis

Rarely posterior uveitis

May occur with arthritis

Occurs in 3-5% of IBD patients

F>M 3:1

Needs ophthalmological assessmentEye: does not correlate well with

disease activity. Episcleritis, uveitis

More common in persons with Crohn’s disease.

Calcium oxalate stones are the most common type of renal calculi

Treatment is to increase hydration and to use oral calcium citrate supplements, which bind the oxalate within the intestinal tract and prevent its excretion in the urinary tract.

Because of its proximity to the ureters, inflammation of the small bowel may involve the ureters, causing obstruction and hydronephrosis.

Fistulae occasionally occur between the bowel and bladder or ureters.

-Sclerosing cholangitisis most commonly associated with ulcerative colitis. 5% of all IBD patients.

Gallstones are common in persons with Crohn disease

Malabsorption may result from extensive ileal resection and produce deficiencies, of fat-soluble vitamins, vitamin B12, or minerals, resulting in anemia, hypocalcemia, hypomagnesemia, clotting disorders, and bone demineralization. In children, malabsorption retards growth and development.

CROHN’S DISEASEDiagnosis

History Physical Findings Contrast Study Endoscopies Surgical specimen and Histology

CROHN’S DISEASE

ILIOSCOPIC FINDINGS

CROHN’S DISEASE INVOLVING ILEUM

CROHN’S DISEASE

Colonoscopic appearance of Crohn’s Disease

CA

PS

ULE E

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OS

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PIC

FIN

GIN

GS

CA

PS

ULE E

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Symptoms Stage

People with mild to moderate Crohn’s disease are able to eat food normally without dehydration, fevers, stomach pain, blockages in their intestines or losing more than 10% of their body weight.

Mild to

Moderate

Crohn’s

DiseasePeople are considered to have moderate to severe Crohn’s disease if they do not respond to treatment for mild to moderate Crohn’s disease or if they have high fevers, significant weight loss, stomach pain or tenderness, occasional nausea or vomiting or significant anemia.

Moderate to

Severe

Crohn’s

DiseasePeople with Severe Crohn’s disease have symptoms despite taking steroids, or have high fevers, persistent vomiting, blockages in their intestines, or an abscess

Severe

Crohn’s

Disease

Goals of Treatment

Remission

Maintenance

Summary of Standard Therapy

Induction of Remission

Maintenance of Remission

Adverse Effects

Steroids Established 70-90%

Ineffective Yes

5-ASA Minor effect Conflicting evidence

Yes

Antibiotics No No

Immune Suppresants

Established 55% Established Yes

Methotrexate Established Not demonstrated

Yes - teratogenic

Biologicals Established Established Yes

CROHN’S DISEASE

The “conventional” Therapeutic Pyramid for Active Crohn’s Disease

Aminosalicylates/Antibiotics

Corticosteroids

Immunomodulators

Surgery

Anti-TNF

Budesonide

Severe

Moderate

Mild

CROHN’S DISEASE

COMPLICATIONS OF CROHN’S DISEASE

Ulcers Fistulas Abscesses Intestinal blockage Extra-intestinal disorders

Inflammation of the eyes, skin, or joints

Malnutrition Growth failure in children

Hanauer SB et al. Am J Gastroenterol. 2001; 96: 635-643.

CROHN’S DISEASE

CROHN’S DISEASE COMPLICATIONS: FISTULAS

A “tunnel” between two sections of the intestines or between the intestines and other organs, including the skin

Data on file, Centocor.West R and Scott NA. Chapter 37. In: Satsangi J, Sutherland LR, eds. Inflammatory Bowel Diseases. 1st ed. Churchill Livingstone, Elsevier; 2003.

CROHN’S DISEASE

ANAL AND PERIANAL FISTULA PRE AND POST TREATMENT

Steroids have serious side effects

• Osteoporosis/osteonecrosis

• Higher risk of infections• Oedema/cushing syndrome

• Cataracts/glaucoma• Growth retardation • Behavioral changes• Striae• Diabetes• Cardiovascular complications

Satsangi et al. Inflammatory Bowel Diseases. Churchill Livingstone, 2003 Yang & Lichtenstein Am J Gastro 2002; 97:803-823 Lukert BP et al. Ann Intern Med. 1990;112:352Sandborn WJ Canadian Journal of Gastroenterology. 14 Suppl C:17C-22C, 2000 Sep

CROHN’S DISEASE

Crohn’s disease usually has a chronic indolent course. Mortality appears to be the highest in the 4-5 years after the diagnosis.

The chance of death and complication with proximal small bowel disease have a higher risk of mortality.

CROHN’S DISEASE

Mortality / Morbidity

As the disease progresses, medical therapy becomes less effective. In the first year after diagnosis, the relapse rate approaches 50%, with 10% of patients having a chronic relapsing course.

Most patients develop complications that require surgery ( approximately 80%)

Crohn’s disease frequently recurs after surgery.

CROHN’S DISEASE

Mortality / Morbidity

Treatment goals in biological treatment era

Sustained Clinical remission off steroids

Intestinal healing

Prevention of complications

Prevention of hospitalization &

surgery

CROHN’S DISEASE

0

2400 12 24 36 48 60 72 84 96108120132144156168180192204216228

100

90

80

70

60

50

40

30

20

10

Progression of Crohn's Disease

Cosnes J, et al. Inflamm Bowel Dis. 2002;8:244-250.

Patients at risk:N= 2002 552 229 95 37

Penetrating

Stricturing

Cu

mu

lati

ve P

rob

ab

ilit

y (

%)

Inflammatory

Months

CROHN’S DISEASE

Timing is important in treating

Crohn’s disease

Biologics

(eg. Infliximab)

Prednisone

Corticosteroids

Budesonide

Surgery

Early

Late

5 -ASA?Antibiotics

AZA/6- MP/

MTX

Aminosalicylates/Antibiotics

Corticosteroids

ImmunomodulatorsSurgery

Anti-TNF

Budesonide

Severe

Moderate

Mild

CROHN’S DISEASETherapy for CD:

A -Conventional Treatment

B -Inverted Pyramid

Therapy for CD: Inverting the Pyramid?

Biologics

(eg. Infliximab)

Prednisone

Corticosteroids

Budesonide

Surgery

Early

Late

5 -ASA?Antibiotics

AZA/6- MP/

MTX

CROHN’S DISEASE

BIOLOGICAL TREATMENT

o Module 1 Selecting patients

o Module 2 Starting patients

o Module 3 Optimizing treatment

o Module 4 Monitoring the patient

o Module 5 Watching for and managing issues

Anti-TNF agents in Crohn's disease are indicated for:Europe: Treatment of severe, active Crohn's disease are

in patients who have not responded despite a full and adequate course of therapy with corticosteroid and/or an immunosuppressant; or patients who are intolerant to or have medical contraindications for such therapies*

US:Reducing signs and symptoms and inducing and

maintaining clinical remission in patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy*

EUROPEAN AND US REGISTRATION

Infliximab is also indicated for fistulating Crohn’s diseaseAdapted from EMEA therapeutic indications, and FDA indications and usage, for Humira and Remicade. Please see EMEA summary of product characteristics and FDA drug product label for Humira and Remicade

RECOGNIZING THE RIGHT INDICATIONS

Do not treat too late1

Tailor treatment to the individual.

Start with widely accepted indications.

1 Schreibers S et. Al. Gastroenterology 2007, 132 (4 Supp): A-147

Early indications of anti-TNF Inhibitors reasonable in: - Steroid – dependency

- Smokers

- Rectal disease

- Parianal lesions

- Extensive small bowel disease

- ileocolonic disease

- Severe upper GI disease

- Younger patients

- Patients with early stricturing / penetrating disease

- Patients with deep colonic ulcers

CROHN’S DISEASE

HOW TO IDENTIFY EARLY THOSE PATIENTS WITH A POOR PROGNOSIS

Young age on onset (<40 years)1

Perianal disease at diagnosis1,2

Severe disease at onset (Weight loss>5kg at presentation, steroids for first attack)1,2

Stricturing disease at diagnosis 2

Deep colonic ulcers3

Extensive disease at diagnosis1,2

Positive predictive value 70-90% if 2 or more factors

present1.2

1. Beaugerie L, et al. Gastroenterology 2006; 130:650-62. 2.Loly C et al. Scand J Gastroenterology 2008; 43:948-543. 3. Allez M, et al. Am J Gastroenterol 2002; 97:947-53

WHAT WE CAN EXPECT FROM ANTI-TNF THERAPY?

In Controlled clinical trials, we see Significant rates of clinical remission and response

1-

3

In anti-TNF naïve and experienced patients Significant rates of steroid-free remission,

4 and

steroid discontianuation5

Decreased risk of hospitalisation5,6

and surgery5,7

Maintenance of efficacyIn addition Anti-TNF therapy may be effective in reducing

extaraintestinal manifestations including arthralgia, arthritis, pyoderma gangrenosum and erythema nodosum

8,9

1. Hanauer S, et al. Gastroenterology 2006; 130:323-33; 2. Hanauer S, et al. Lancet 2002;359:1542-9.3 Colombel J-F, et al. Gastroenterology 2007 ;132:52—65; 4. Kamm M, et al. J Crohns colitis 2009;3:S43: 5. Rutgeerts et al. Gastroenterology 2004;126:402—13; 6. Fegan B, et al. Gastroenterology 2007;132:A –513(T1312); 7. Schreiber S, et al. am J Gastroenterol 2008;103(Suppl 1):S379(#965); 8. Louis E, et al. J Crohns Collitis 2009;3”:S57; 9. Siemanowski B, Regueiro M. Curr Treat Options Gastroenterol 2007;10:178--84

TNF- Binding Proteins

Adalimumab

(Humira®)

Infliximab

(Remicade®)

5 mg/kg BW i.v.

Week 0, 2, 6

than every 8 weeks

160 or 80 mg s.c. 1x

than 80 or 40 mg 1x

than 40 mg s.c. eow

ANTI- TNF THERAPY: DOSE

Subcutaneous (adalimumab)

In patients with a severe flare or for a more rapid response:

- 160mg at week 0 followed by 80 mg at week 2- Then a 40mg every other week

1

In patients with less severe breakthrough symptoms: - 80mg at week 0 followed by 40mg at week 2- Then 40mg every other week

Intravenous (infliximab)2,3

5mg/kg at 0 weeks, 2 weeks and 6 weeks Then 5mg/kg every 8 weeks

1. Hanauer S,et al. Gastroenterology 2006; 130:323-332. Rutgeerts P, et al. Gastroenterology 2004; 126: 402-133. Hanauer SB, et al. Lancet 2002; 359:1541-9; EMEA SPC, Humira & Remicade

CHARM: CD – RELATED HOSPITALIZATION AND SURGERY

ANTI- TNF THERAPY: EXCLUSION CRITERIA

Heart failure Current malignancy Active infectious disease Latent or active tuberculosis Abscess Pregnancy * Previous malignancy:* Previous breast cancer, or other malignancies 1 within past 5 years Multiple sclerosis Active Hepatitis B infection

Sources include: EMEA SPC, Humira & Remicade* Relative contraindications* Excluding non-melanoma skin cancer

ANNUAL RISK OF LYMPHOMA WITH ANTI-TNF THERAPY (WORST-CASE)

Ten thousand People

The paling Palette of 10,000 people. www.riskcomm.com

BASELINE EXAMINATION : PERIANAL FISTULAE

If perianal fistulae are present, exclude abscessDetermination may entail: Clinical examination under anesthesia and/or Imaging (MRI or endoscopic ultrasound)

If abscess is present: Ensure full drainage Consider leaving a loose seton in place, at

least until the end of induction therapy Consider transit Co-treatment with

antibiotics

USE OF CONCOMITANT IMMUNOSUPPRESSANT'S 1

If the patient is immunosuppressant-naïve

Start anti-TNF monotherapy or start anti-TNF/immunosuppressant combined therapy

The choice is based on a risk/benefit evaluation for each patient

-- Combined therapy is more efficacious-- However, it may be associated with a higher risk of lymphoma, including hepatosplenic T-cell lymphoma,

1 and(possibly) of

opportunistic infection2

-- Favour combined therapy in patients with severe extensive disease, in whom rapid healing is very important If using combined therapy, consider stopping one drug after

6-12 months-- Cessation of immunosuppressant does not appear to affect clinical outcome

3

-- Cessation of anti-TNF agent has not been adequately evaluated, but should be preceded by careful evaluation to confirm complete endoscopic and biological disease control

4

1. Mackry AC, et al. J Ped Gastroenterol Nutr 2007; 44:265-7 2. Toruner M, et al. Gastroenterolgy 2006; 130:A-71 [Abstract #489]

3. Van Assche G, et al. Gastroenterology 2008; 134:1861-8 4. Louis E, et al. DDW 2009; Abstract 961

USE OF CONCOMITANT IMMUNOSUPPRESSANT'S 2

ACCENT I & II: EFFECT OF CONCOMITANTIMMUNOSUPPRESSANTS WITH INFLIXIMAB

MAINTAINING REMISSIONWith regular maintance therapy: Remission with anti-TNF agents can be

maintained through at least 3 years of treatment (based on data available adalimumab)

1

There is no good medical reason to stop anti-TNF therapy in patients showing good efficacy and toleranceIf treatment cessation is considered for any reason:

First aim for stable, steroid-free remission for at least 1 year

2

Assess CRP levels and perform endoscopy, and avoid cessation if any sign of disease activity

2

CRP = C-reactive protein1. Panaccione R, et al. J Crohn’s Colitis 2009; 3:S69-S70; 2. Louis E, et al. DDW 2009; Abstract 961

“TOP-DOWN” VERSUS “STEP-UP”STRATEGY, INFLIXIMAB

BASELINE MONITORING: DISEASE ACTIVITY

(HARVEY BRADSHAW INDEX)

Remission <5Mild Disease 5 – 7

Moderate Disease 8 – 16Severe Disease >16

WHAT HAPPENS IF: INFUSION REACTION

Slow down or interrupt the infusion if: Mild acute reaction (monitor as appropriate)

Stop the infusion if: Moderate or severe acute reaction(Hydrocortisone or other treatment as appropriate)

Delayed reaction: Intravenous or oral steroids

Prophylaxis before next dose of Infliximab: Antihistamine and hydrocortisoneEMEA Summary of product characteristics (SPC), Remicade 100mg powder for concentrate for

solution for infusion

Remicade (Infliximab) Safety Hypersensitivity

Allergic reaction at time of infusion – 5% Autoimmune syndromes

Lupus like illness – rare and recovers on stopping on therapy

Infection Profound immunosuppression occurs Opportunistic infections can occur Tuberculosis high risk Hepatitis B can be reactivated

Cancer Recent data suggests that overall cancer rates

may be reduced Hepatosplenic T-cell lymphomas – 1 in 20000

patients

Patient Exposure since Launch: Therapeutic Area - Worldwide

Post-marketing surveillance

* EU includes Norway, ROW includes Japan and Canada

Cumulative Since Launch: 24 Aug 1998-23 Feb 2009

Total treated patients - Worldwide: 1,153,934

Data on file, Centocor (PSUR 19, April 2009).

Luminal CD

Mild

Moderate

Severe

Budesonide(R. colon/ileal)Sulfasalazine(left colon)

Symptoms

Burden of Disease

History

Anti-TNFScheduledMaintenance

Prednisone

FAIL 4–8 wk

1-2wk steroi

ds

Panaccione, Rutgeerts, Sandborn, Feagan, Schreiber, Ghosh APT 2008

MTX × 12 WeeksOr

AZA × 16 Weeks

Moderate CD Algorithm: Time Bound

Moderate

Prednisone

CorticosteroidRefractory

CorticosteroidDependent

Anti-TNFScheduledMaintenance

MTX × 12 WeeksOr

AZA × 16 Weeks

2–4

W

eeks

16–2

4

Weeks

Respondand Taper

FAIL

Panaccione, Rutgeerts, Sandborn, Feagan, Schreiber, Ghosh APT 2008

Predictors of very severe Crohn’s Disease

- >70cm resection, >2 resections, colectomy, stoma,

complex perianal disease.

- 18% of patients at 5 years.

- Independent predictors at diagnosis:

- Age <40

- Stricturing or intra-abdominal penetrating

- Fever

- Loss of >5kg

- Increased platelets counts

Infliximab in Patient with Fistulizing Crohn’s Disease Before & After

treatment

CROHN’S DISEASE

Conclusions- Poor disease control leads to development of

complications, severe disease and disability

- Selecting patients for an appropriate treatment strategy is critical to achieving optimal disease control

- Early treatment in appropriate patients appears to avoid some of the worst outcomes of the disease

- Anti-TNF therapy appears to help us achieve long-term, steroid-free remission and possible mucosal healing

- Scheduled maintenance therapy appears more effective than episodic treatment

- Concomitant immunosuppression may be beneficial in selected cases

- There are no data supporting stopping therapy, although early intensive treatment with anti-TNF in RA maintained remission without therapy

Thank You

Cumulative risk of intestinalresection

Cosnes et al. Gut 2005

1978-1982 n=2231993-1997 n=530

1983-1987 n=330 1998-2002 n=335

1988-1992 n=480

CD

-rela

ted

su

rgeri

es (

% p

at.

)

Month after diagnosis

0

10

20

30

40

50

0 12 24 36 48 60 72

CROHN’S DISEASE

A Significant Number of CD Patients Suffer Unemployment and Need Social

Welfare

Feagan BG, et al. J Clin Gastroenterol. 2005;39:390–395.

Prior bowel resection is associated with a higher likelihood of unemployment and of receiving disability

compensation

48% Full Time

13%Part

Time 39%Unemployed

75% Not Receiving

Disability

25% Receiving

Disability

Employment DisabilityCompensation

Hypersensitivity Autoimmune syndromes

Lupus like illness – rare and recovers on stopping on therapy

Infection Profound immunosuppression occurs Opportunistic infections can occur Tuberculosis high risk Hepatitis B can be reactivated

Cancer Recent data suggests that overall cancer rates may be

reduced Hepatosplenic T-cell lymphomas

CROHN’S DISEASE

Patient Exposure since Launch: Therapeutic Area - Worldwide

Post-marketing surveillance

* EU includes Norway, ROW includes Japan and Canada

Cumulative Since Launch: 24 Aug 1998-23 Feb 2009

Total treated patients - Worldwide: 1,153,934

Data on file, Centocor (PSUR 19, April 2009).

Luminal CD

Mild

Moderate

Severe

Budesonide(R. colon/ileal)Sulfasalazine(left colon)

Symptoms

Burden of Disease

History

Anti-TNFScheduledMaintenance

Prednisone

FAIL 4–8 wk

1-2wk steroi

ds

Panaccione, Rutgeerts, Sandborn, Feagan, Schreiber, Ghosh APT 2008

MTX × 12 WeeksOr

AZA × 16 Weeks

CROHN’S DISEASE

Predictors of very severe Crohn’s Disease

- >70cm resection, >2 resections, colectomy, stoma, complex perianal disease.

- 18% of patients at 5 years.

- Independent predictors at diagnosis:

- Age <40

- Stricturing or intra-abdominal penetrating

- Fever

- Loss of >5kg

- Increased platelets counts

0

2400 12 24 36 48 60 72 84 96108120132144156168180192204216228

100

90

80

70

60

50

40

30

20

10

Progression of Crohn's Disease

Cosnes J, et al. Inflamm Bowel Dis. 2002;8:244-250.

Patients at risk:N= 2002 552 229 95 37

Penetrating

Stricturing

Cu

mu

lati

ve P

rob

ab

ilit

y (

%)

Inflammatory

Months

CROHN’S DISEASE

WHAT COULD BE THE OTHER OPTIONS IN

MANAGEMENT OF CROHN’S

DISEASE?

Non-Drug Approaches – Cigarette Smoking

Smokers with Ulcerative Colitis

Have less relapses Smokers with Crohn’s

disease Have more relapses Disease more difficult to

treat Stopping smoking

reported to have same effect on Crohn’s disease as giving steroids.

Probiotics

TRICHURIS SUIS OVA (TSO)

Fish Oil

WHAT COULD BE THE OTHER OPTIONS IN MANAGEMENT OF

CROHN’S DISEASE?

Diseases and conditions where stem cell treatment is promising or emerging.[38] Bone marrow transplantation is, as of 2009, the only established use of stem cells.

:// . - . / / - - - - .http www news medical net health What are Embryonic Stem Cells aspx

Thank You

Incidence5-15 / 100 000 population1

Prevalence9 – 199 / 100 000 population1

1 Marshall JK and Hilsden RJ. Chapter 2. In: Satsangi J, Sutherland LR, eds .Inflammatory Bowel Diseases. 1st ed. Churchill Livingstone, Elsevier; 2003. p.18

2 Economou M and Pappas G, Inflammatory Bowel Diseases. 2008; 14: 709-720.

Global map of CD2

Annual incidence:- red >7/105

- orange 4-7/105

- green 1-4/105

- blue <1/105

- white absence of data

CROHN’S DISEASE

Incidence & Prevalence

WHERE IS 11 E??

IBD is an idiopathic & inflammatory disorder of GIT, comprise primarily UC & CD

Approximately 1 million people in the USA have been diagnosed with IBD & an additional 30,000 people are newly diagnosed each year.

CROHN’S DISEASE

Introduction

Highest age adjusted incidence rate of IBD (15-30) overlap reproductive years.

Improved Medical & Surgical treatment of IBD has allowed pts with more significant illness to consider pregnancy & having children.

Optimal management of reproductive health in IBD pts is a challenge to gastroenterologist obstetrician & IBD surgeons.

CROHN’S DISEASE

Introduction

CD: INCIDENCE & PREVALENCE

Incidence5-15 / 100 000 population1

Prevalence9 – 199 / 100 000 population1

1 Marshall JK and Hilsden RJ. Chapter 2. In: Satsangi J, Sutherland LR, eds .Inflammatory Bowel Diseases. 1st ed. Churchill Livingstone, Elsevier; 2003. p.18

2 Economou M and Pappas G, Inflammatory Bowel Diseases. 2008; 14: 709-720.

Global map of CD2

Annual incidence:- red >7/105

- orange 4-7/105

- green 1-4/105

- blue <1/105

- white absence of data

CROHN’S DISEASE

THE ROLE OF PRO-INFLAMMATORY CYTOKINES IN CROHN’S DISEASE

Sands BE et al. Inflammatory Bowel Diseases. 1997; 3: 95-113. Feldmann M et al. Adv Immunol. 1997; 64: 283-350.

CROHN’S DISEASE

Add the second conclusion slide 74

TREATING CD B1,2,3

Fish Oil What is it?

Derived from fish Contains omega-3 fatty

acids What do they do?

Anti-inflammatory effect Reduces leukotriene B4

How do you take it? Enteric coated capsules

to avoid “fishy smell”

0

10

20

30

40

50

60

%

Fish Oil Placebo

Patients in Remission at 1 Year

CAPSULE ENDOSCOPY

FINDINGS

Probiotics

“...living micro-organisms which upon ingestion in certain numbers exert health benefits beyond

inherent general nutrition…”

Copyright © 2009 Elsevier B.V.

Pig whipworm ova taken as a drink

Does not survive long in humans

Need repeated drinks High rate of remission

reported 50% in UC, 70% in

Crohn’s Intestinal helminths

induce cytokine release and down regulate cell mediated responsiveness

http://www.slideworld.org/viewslides.aspx/Treatment-of-Inflammatory-Bowel-Disease-ppt-28078

TRICHURIS SUIS OVA (TSO)

REGENERATIVE MEDICINE

Arthritis Axial – Ankylosing

Spondylitis Peripheral

Skin Erythema nodosum Pyoderma

gangrenosum Eyes

Anterior uveitis Episcleritis/Iritis

Liver PSC Autoimmune

hepatitis

Common Extra G.I. Complications

Extraintestinal manifestations of IBD are important to consider in the management of patients with Crohn's disease and ulcerative colitis. They are most commonly associated with active bowel disease, but can also occur prior to bowel disease or during periods of remission. Although management typically involves control of the active disease, there are treatment options for those patients who continue to be symptomatic despite treatment of their bowel disease

Drug Therapies

Glucocorticoids (steroids)

5-aminosalicylates (5-ASA)

Immunosuppressants

Antibiotics

Biological Therapy

Steroid Effectiveness

Highly effective for the induction of remission in patients with active disease

Short-term response rates (12–16 weeks) range from 70–90%

Not effective in maintenance of remission

5-ASA Drugs

Sulphasalazine first agent discovered Group now includes:

Pentasa (mesalazine) Asacol (mesalazine) Dipentum (olsalazine) Salazopyrin-EN (sulphasalazine)

Work locally on the lining of the gut to reduce inflammation

Immune Therapy for Crohns Disease

TNF-α is a key mediator of inflammation TNF-α expressed in bowel wall in Crohns

disease and faecal concentrations reflect disease severity

Products neutralising TNF-α are beneficial in treatment of Crohns disease

Infliximab (Remicade) infusion

Remicade (Infliximab) Safety Hypersensitivity

Allergic reaction at time of infusion – 5% Autoimmune syndromes

Lupus like illness – rare and recovers on stopping on therapy Infection

Profound immunosuppression occurs Opportunistic infections can occur Tuberculosis high risk Hepatitis B can be reactivated

Cancer Recent data suggests that overall cancer rates may be reduced Hepatosplenic T-cell lymphomas – 1 in 20000 patients

TNF- binding proteins

Adalimumab

(Humira®)

Infliximab

(Remicade®)

5 mg/kg BW i.v.

Week 0, 2, 6

than every 8 weeks

160 or 80 mg s.c. 1x

than 80 or 40 mg 1x

than 40 mg s.c. eow

Treatment goals in biological treatment era

Sustained Clinical remission off steroids

Intestinal healing

Prevention of complications

Prevention of hospitalization &

surgery

Luminal CD

Mild

Moderate

Severe

Budesonide(R. colon/ileal)Sulfasalazine(left colon)

Symptoms

Burden of Disease

History

Anti-TNFScheduledMaintenance

Prednisone

FAIL 4–8 wk

1-2wk steroi

ds

Panaccione, Rutgeerts, Sandborn, Feagan, Schreiber, Ghosh APT 2008

MTX × 12 WeeksOr

AZA × 16 Weeks

Moderate CD Algorithm: Time Bound

Moderate

Prednisone

CorticosteroidRefractory

CorticosteroidDependent

Anti-TNFScheduledMaintenance

MTX × 12 WeeksOr

AZA × 16 Weeks

2–4

W

eeks

16–2

4

Weeks

Respondand Taper

FAIL

Panaccione, Rutgeerts, Sandborn, Feagan, Schreiber, Ghosh APT 2008

Conclusions- Poor disease control leads to development of

complications, severe disease and disability

- Selecting patients for an appropriate treatment strategy is critical to achieving optimal disease control

- Early treatment in appropriate patients appears to avoid some of the worst outcomes of the disease

- Anti-TNF therapy appears to help us achieve long-term, steroid-free remission and possible mucosal healing

- scheduled maintenance therapy appears more effective than episodic treatment

- Concomitant immunosuppression may be beneficial in selected cases

- There are no data supporting stopping therapy, although early intensive treatment with anti-TNF in RA maintained remission without therapy

PILES – LEADING TO MASSIVE G.I BLEEDING

CROHN’S DISEASE INVOLVING ILEUM